The present invention relates to an oral composition which is effective against halitosis (oral malodor, foetor ex ore). Said composition is effective by eliminating or reducing the production of volatile sulfur compounds (VSCs) in the oral cavity. It is well established that in the majority of cases of halitosis this originates from the oral cavity and not from the stomach, as frequently believed by the public.
Bacteria located in the crypts at the back of the tongue and in periodontal pockets produce VSCs, mainly hydrogen sulfide (HS) and methyl mercaptan (MM). The bacteria produce these by proteolytic, anaerobic metabolism, and they have an extremely unpleasant odor even in very low concentrations. The VSCs are able to penetrate epithelium and have pathogenic potentials by damaging cells of the underlying tissues and also affect their metabolism. It has been suggested that the VSCs produced by bacteria in periodontal pockets may well be an important factor in the development of periodontal disease. MM appears to have a higher pathogenic potential than HS and has also a more offensive odor.
The most important substrate for HS production in the oral cavity appears to be cysteine. HS forms immediately upon rinsing the mouth with an aqueous solution of this amino acid (see example 2). Methionine is a major substrate for MM formation, although this compound is not as rapidly formed in the oral cavity as hydrogen sulfide.
It Is known that zinc ions reduce the VSC production in the oral cavity. The mechanism involved presumably involves a reaction between zinc and sulfur whereby non-volatile sulfides are formed and thus inhibit the transformation of sulfur containing substrates to VSCs. Zinc furthermore possesses a certain antibacterial activity and this metal ion is known to be able to inhibit plaque formation and reduce acid formation in dental plaque. The zinc salts usually used for such purposes are the chloride, the sulfate and the citrate. However, aqueous solutions of the two former salts have low pH and are thus not necessarily suited for oral use whereas solutions of zinc citrate contain complexes of zinc and citrate and very few free zinc ions.
The problem of getting zinc in a suitable form is the issue of U.S. Pat. No. 4,289,753 and UK Patent Application No. 2,052,978. In the former the zinc compound used is an ammonium or alkali metal citrate. It is also stated In this patent that this zinc compound may be used in combination with antibacterial agents such as cetyl pyridinium chloride.
The above UK Patent Application discloses an oral composition in which the pH of a zinc containing solution is adjusted to 4.5 or 8 by means of glycine. The zinc is generally present as zinc chloride.
Antibacterial agents such as cationic bis-biguanides and quaternary ammonium compounds, have been widely used in preventive dentistry as inhibitors of plaque formation and of development of gingivitis. The bis-biguanide chlorhexidine is frequently used for this purpose, usually as an aqueous solution of 0.2% of its gluconate salt, and is applied as a mouthrinse twice daily. Such concentration and frequency are necessary to obtain consistent clinical plaque inhibition. However, chlorhexidine in these concentrations has a bitter taste and causes dental stain. Chlorhexidine forms salts of low solubility with chloride, sulfate and citrate and is thus not compatible with zinc containing these anions.
The other cationic antibacterial agents which inhibit plaque formation, for example cetylpyridinium chloride or benzalkonium chloride, have less clinical effect, but show a less pronounced tendency to cause dental stain. The cationic antibacterial agents mentioned above are able to inhibit VSC formation in the oral cavity, but relatively high concentrations are needed (see Example 1).
It has now unexpectedly been found that anti-VSC effect of zinc Ions Is mainly directed against hydrogen sulfide production and to a far lesser extent against the production of methyl mercaptan (see Example 1, FIG. 2). The VSC species with highest pathogenic potential and the most unpleasant odor i.e. MM, is thus incompletely eliminated by zinc ions.
This selective effect on HS by zinc can presumably be explained by the fact that cysteine (which is major substrate for HS formation) has an exposed xe2x80x94SH group, which will react readily with zinc ions, whereas methionine (which is a substrate for MM formation) has no such group. When hydrogen sulfide Is dissolved in water (or saliva) HSxe2x80x94 and Sxe2x80x94 are formed (together with two protons), and both these sulfur containing intermediates react rapidly with zinc ions to form insoluble sulfides.
It was furthermore unexpectedly found that when a combination of zinc ions and very low concentrations of certain cationic antibacterial agents were used, the combinations inhibited both HS and MM formation. The effect of the combinations is synergistic (Example 1, table 1) The combinations of zinc and low concentrations of antibacterial agent caused a much higher inhibition of VSCs than any of the individual agents alone. The concentration of an antibacterial agent used in this way against oral malodor was markedly lower than the concentrations needed to obtain plaque inhibition or reduced acid formation in plaque ({fraction (1/10)} or less).
The importance of this invention resides in the fact that It allows the use of very low concentrations of antibacterial agents, i.e. concentrations where their undesired side effects are avoided. The contribution of the antibacterial agent is probably mainly to inhibit MM formation, but synergistic effect with zinc against HS was also observed, although not to the same degree as against MM. The concentration of zinc can also be kept lower than when zinc is used alone, for the same reason. Zinc has a metallic taste which is concentration dependent.
The use of combinations of zinc acetate and chlorhexidine is described in DE 30001575 A1. However, the purpose is to avoid discoloration of teeth by chlorhexidine. In U.S. Pat. No. 4,522,806 an anti-plaque effect of the combination of chlorhexidine and zinc acetate is mentioned (page 5, first paragraph). The combination was found to be numerically better than chlorhexidine alone, but the difference was not statistically significant.
In U.S. Pat. No. 5,906,811 a combination of zinc acetate and benzalkoniumchloride is mentioned as an ingredient in tooth-pastes. The main purpose is to avoid damage from free radical species on the oropharyngeal cavity of tobacco smokers, including secondary smokers.
The present invention provides an oral composition for inhibiting oral malodor, comprising an antibacterial agent and a zinc compound. The composition is in the form of a mouthwash containing 0.005-0.05% wt of an antibacterial agent selected from bis-biguanides and quaternary ammonium compounds, and 0.05-0.5% w/v zinc acetate.
When zinc acetate is used together with an antibacterial agent selected from the bis-biguanides or quaternary ammonium compounds, the effect appears to be synergistic, as mentioned above. This means that by using such a combination, the amount of both (i.e. zinc acetate and anti-bacterial agent) may be kept very low. By using such low amounts the bitterness of the taste and the tendency to cause dental stain will both be avoided.
A major benefit of this invention is that it allows the use of much lower concentrations of antibacterials In compositions specially designed to inhibit oral malodor, than in ordinary products intended for anti-plaque and anti-gingivitis purposes.
The low concentrations of the antibacterial agent is favorable both from an economical and toxicological point of view. The presence of zinc in itself reduces the tendency to cause dental stain, because zinc sulfide is white or gray, whereas the other metal sulfides which form on teeth are black, brown or yellow.
As mentioned above it is a great advantage that the concentrations of the two ingredients, in particular the concentration of the antibacterial agent, can be kept very low, This is particularly easy to control in a mouthrinse where the concentrations of said active ingredients can be readily adjusted to the desired value. According to a particularly preferred embodiment the oral composition of the invention is in the form of a mouthrinse containing from 0.01% to 0.025% w/v of the antibacterials and 0.1% to 0.3% w/v of zinc acetate.
As mentioned above, a preferred antibacterial agent is chlorhexidine or a salt thereof, in particular the acetate or the gluconate salts. Preferred quaternary ammonium compounds are cetyl pyridinium chloride or benzalkonium chloride.
According to another embodiment of the invention a composition comprising an antibacterial agent selected from the bis-biguanides and the quaternary ammonium compounds, and zinc acetate, is used for the preparation of an oral composition in particular in a mouthrinse, for inhibiting oral malodor.
In a further embodiment of the invention a composition containing an antibacterial agent selected from bis-biguanides an quaternary ammonium compounds, and zinc acetate, is used for the treatment of oral malodor. In the use indicated above, the amounts of the components should be as described above in connection with the oral composition.